The present invention relates to novel and heretofore unavailable 2-guanidino-4-(2-substituted-amino-4-imidazolyl)thiazoles; a novel process therefor, also having advantages in the preparation of known compounds which are lower homologs thereof; and intermediate compounds useful in this novel process. These compounds have activity as antisecretory agents, histamine-H.sub.2 antagonists and/or inhibitors of ethanol-induced gastric ulceration in rats and so are useful in inhibiting (i.e., preventing and treating) peptic ulcers.
Chronic gastric and duodenal ulcers, together known as peptic ulcers, are a common ailment for which a variety of treatments, including dietary measures, drug therapy and surgery, may be employed, depending on the severity of the condition. Particularly valuable therapeutic agents useful for the treatment of gastric hyperacidity and peptic ulcers are the histamine-H.sub.2 receptor antagonists, which act to block the action of the physiologically active compound histamine at the H.sub.2 -receptor sites in the animal body and to thereby inhibit the secretion of gastric acid. The determination that many of the present compounds will also inhibit ethanol-induced ulcers in rats, further reflects the clinical value of the present compounds in the inhibition of gastric ulcers.
Compounds of the present class, having the formula ##STR1## wherein R.sup.a is H, (C.sub.1 -C.sub.6)alkyl, or (C.sub.7 -C.sub.10)phenylalkyl, said phenyl groups optionally monosubstituted with chloro, bromo, fluoro, (C.sub.1 -C.sub.3)alkyl or (C.sub.1 -C.sub.3)alkoxy, have been previously described as antiulcer agents, by dint of their antisecretory and histamine-H.sub.2 antagonist activity. LaMattina and Lipinski, U.S. patent applications Ser. Nos. 196,231 filed Oct. 14, 1980, now abandoned, and 293,574, filed Aug. 20, 1981, now U.S. Pat. No. 4,374,843, issued Feb. 22, 1983 and corresponding to European Patent Application No. 50,458, published Apr. 28, 1982.
The novel process of the present invention is advantageous in the preparation of compounds of the formula (I), particularly when R.sup.a is (C.sub.3 -C.sub.6)alkyl or (C.sub.7 -C.sub.10)phenylalkyl. Furthermore, the present process permits preparation of structurally related compounds of the formula (II), below, which are not available by the processes earlier disclosed in the above cited U.S. applications.
Key to the present process is the discovery that a primary or secondary amine will react with 2-amino-5-acetyloxazole, of the formula (IV) below, to form the intermediate 2-(substituted-amino)-5-acetylimidazole of the formula (V) below. Heretofore, no such reaction has been observed. The ring oxygen of 2-methyloxazole-4-carboxylic acid has been replaced with NH and then with NC.sub.6 H.sub.5 under similar conditions with concommitant decarboxylation. Cornforth and Cornforth, J. Chem. Soc. 1947: 96-102.